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Study of the Molecular Mechanisms of the Therapeutic Properties of Extracellular Vesicles

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (1 September 2022) | Viewed by 21615

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Dr. Denis N. Silachev

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1. Laboratory of Biochemistry of Motor Systems, A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
2. Laboratory Stem Cells Technology, V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
Interests: extracellular vesicles; cerebral ischemia; stroke; brain trauma; mitochondrial traffic; neuroprotection; ischemic preconditioning; autophagy; aging; intercellular communication
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Dear Colleagues,

Extracellular vesicles are currently one of the most studied cellular derivatives in terms of various aspects of cellular physiology, and they are considered to represent a new mode of intercellular communication. Extracellular vesicles are commonly found, and the term refers to a heterogeneous group of cell-derived membranous structures that includes exosomes and microvesicles. In spite of this, the methodology for isolating cellular vesicles has not yet been standardized, and it is difficult to separate the studied objects by origin based only on linear dimensions and their mass due to overlap in these parameters. The possibility of using extracellular vesicles of stem/progenitor and somatic cells as therapeutic tools with a wide range of cytoprotective and regenerative properties has been convincingly demonstrated. This has prompted the search for “therapeutic” molecules in extracellular vesicles. However, this task is complicated by the complex composition of extracellular vesicles, which includes lipids, proteins, and nucleic acids. The results of research are also contradictory, with some studies demonstrating the key role of miRNA while others completely exclude the contribution of miRNA to the signaling/therapeutic effects of extracellular vesicles. The fundamental question is understanding the contribution of lipids, proteins, and microRNA, which will determine further strategies for creating biomedical drugs based on extracellular vesicles.

In this regard, we invite investigators to contribute original research articles and review articles that will stimulate continuing efforts to understand the role of lipids, proteins, or nucleic acids in the observed therapeutic effects, alone or in combination. Submissions on studies aimed at creating cellular model systems that allow for targeted control of the cargo of extracellular vesicles will be welcomed. Also of interest are submissions on the use of inhibitory analysis and omics technologies with bioinformatics analysis to identify signaling pathways in recipient cells and molecules in extracellular vesicles involved in therapeutic effects.

Dr. Denis N. Silachev
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

exosomes
ectosomes
vesicles
lipids
proteins
nucleic acids
drug delivery
stem cell
regenerative therapeutics

Published Papers (9 papers)

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Editorial

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4 pages, 198 KiB

Open AccessEditorial

Study of the Molecular Mechanisms of the Therapeutic Properties of Extracellular Vesicles

by Denis N. Silachev

Int. J. Mol. Sci. 2023, 24(8), 7093; https://doi.org/10.3390/ijms24087093 - 12 Apr 2023

Cited by 1 | Viewed by 1144

Abstract

Extracellular vesicles (EVs) are small biological structures that are released by cells and have important roles in intercellular communication [...] Full article

(This article belongs to the Special Issue Study of the Molecular Mechanisms of the Therapeutic Properties of Extracellular Vesicles)

Research

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15 pages, 1247 KiB

Open AccessArticle

Extracellular Vesicles from 50,000 Generation Clones of the Escherichia coli Long-Term Evolution Experiment

by David Laurin, Corinne Mercier, Nyamekye Quansah, Julie Suzanne Robert, Yves Usson, Dominique Schneider, Thomas Hindré and Béatrice Schaack

Int. J. Mol. Sci. 2022, 23(23), 14580; https://doi.org/10.3390/ijms232314580 - 23 Nov 2022

Cited by 3 | Viewed by 1630

Abstract

Extracellular vesicles (EVs) are critical elements of cell–cell communication. Here, we characterized the outer membrane vesicles (OMVs) released by specific clones of Escherichia coli isolated from the Long-Term Evolution Experiment after 50,000 generations (50K) of adaptation to glucose minimal medium. Compared with their ancestor, the evolved clones produce small OMVs but also larger ones which display variable amounts of both OmpA and LPS. Tracking ancestral, fluorescently labelled OMVs revealed that they fuse with both ancestral- and 50K-evolved cells, albeit in different proportions. We quantified that less than 2% of the cells from one 50K-evolved clone acquired the fluorescence delivered by OMVs from the ancestral strain but that one cell concomitantly fuses with several OMVs. Globally, our results showed that OMV production in E. coli is a phenotype that varies along bacterial evolution and question the contribution of OMVs-mediated interactions in bacterial adaptation. Full article

(This article belongs to the Special Issue Study of the Molecular Mechanisms of the Therapeutic Properties of Extracellular Vesicles)

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12 pages, 1381 KiB

Open AccessArticle

Microbiota-Derived Extracellular Vesicles Detected in Human Blood from Healthy Donors

by Béatrice Schaack, Thomas Hindré, Nyamekye Quansah, Dalil Hannani, Corinne Mercier and David Laurin

Int. J. Mol. Sci. 2022, 23(22), 13787; https://doi.org/10.3390/ijms232213787 - 09 Nov 2022

Cited by 11 | Viewed by 2520

Abstract

The microbiota constitutes an important part of the holobiont in which extracellular vesicles (EVs) are key players in health, especially regarding inter- and intra-kingdom communications. Analysis of EVs from the red blood cell concentrates of healthy donors revealed variable amounts of OmpA and LPS in 12 of the 14 analyzed samples, providing indirect experimental evidence of the presence of microbiota EVs in human circulating blood in the absence of barrier disruption. To investigate the role of these microbiota EVs, we tracked the fusion of fluorescent Escherichia coli EVs with blood mononuclear cells and showed that, in the circulating blood, these EVs interacted almost exclusively with monocytes. This study demonstrates that bacterial EVs constitute critical elements of the host–microbiota cellular communication. The analysis of bacterial EVs should thus be systematically included in any characterization of human EVs. Full article

(This article belongs to the Special Issue Study of the Molecular Mechanisms of the Therapeutic Properties of Extracellular Vesicles)

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19 pages, 3355 KiB

Open AccessArticle

MicroRNA in Extracellular Vesicles from Patients with Pulmonary Arterial Hypertension Alters Endothelial Angiogenic Response

by Avinash Khandagale, Padraic Corcoran, Maryam Nikpour, Anders Isaksson, Gerhard Wikström, Agneta Siegbahn and Christina Christersson

Int. J. Mol. Sci. 2022, 23(19), 11964; https://doi.org/10.3390/ijms231911964 - 08 Oct 2022

Cited by 7 | Viewed by 2005

Abstract

Pulmonary arterial hypertension (PAH) is characterized by a progressive elevation of pulmonary pressure leading to right ventricular dysfunction and is associated with a poor prognosis. Patients with PAH have increased numbers of circulating extracellular vesicles (EVs) and altered expression of circulating microRNAs (miRs). The study aimed to evaluate the miR profile contained within purified EVs derived from the plasma of PAH patients as compared to healthy controls (HC). Circulating EVs, purified from platelet-free plasma were analyzed using flow cytometry, western blot, and electron microscopy. Total RNA isolated from EVs was subjected to Microarray analysis using GeneChip miRNA 4.0 Array and bioinformatics tools. Overexpression and inhibition of miRs were conducted in human pulmonary artery endothelial cells (hPAECs) that had been incubated previously with either PAH- or HC-derived EVs. Cell proliferation (MTT assay) and angiogenesis (tube formation assay) were tested in hPAECs to determine miR functionality. MiR profiling revealed 370 heats while comparing PAH and HC groups, 22 of which were found to be down-regulated and 6 were up-regulated in the PAH EVs. Among the altered miRs, miR-486-5p was overexpressed, while miR-26a-5p was downregulated in PAH EVs compared to HC EVs. Inhibition of mir-486-5p or overexpression of miR-26a-5p in hPAECs post-exposure of PAH EVs abrogated proangiogenic and proliferative effects posed by PAH EVs contrary to HC EVs. The angiogenic and proliferative effects of the miRs from PAH EVs were observed to be mediated through nuclear factor (NF)-κB activation. PAH EVs carry and present an altered miR profile that can be targeted to restrict angiogenesis and reduce pulmonary endothelium activation. Further studies concerning miRs from circulating heterogeneous EVs in PAH patients are warranted to understand their potential as targets for treatment in PAH. Full article

(This article belongs to the Special Issue Study of the Molecular Mechanisms of the Therapeutic Properties of Extracellular Vesicles)

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16 pages, 2848 KiB

Open AccessArticle

N-Glycans in Immortalized Mesenchymal Stromal Cell-Derived Extracellular Vesicles Are Critical for EV–Cell Interaction and Functional Activation of Endothelial Cells

by Marta Clos-Sansalvador, Sergio G. Garcia, Miriam Morón-Font, Charles Williams, Niels-Christian Reichardt, Juan M. Falcón-Pérez, Antoni Bayes-Genis, Santiago Roura, Marcella Franquesa, Marta Monguió-Tortajada and Francesc E. Borràs

Int. J. Mol. Sci. 2022, 23(17), 9539; https://doi.org/10.3390/ijms23179539 - 23 Aug 2022

Cited by 9 | Viewed by 2343

Abstract

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EV) are widely considered as a cell-free therapeutic alternative to MSC cell administration, due to their immunomodulatory and regenerative properties. However, the interaction mechanisms between EV and target cells are not fully understood. The surface glycans could be key players in EV–cell communication, being specific molecular recognition patterns that are still little explored. In this study, we focused on the role of N-glycosylation of MSC-EV as mediators of MSC-EV and endothelial cells’ interaction for subsequent EV uptake and the induction of cell migration and angiogenesis. For that, EV from immortalized Wharton’s Jelly MSC (iWJ-MSC-EV) were isolated by size exclusion chromatography (SEC) and treated with the glycosidase PNGase-F in order to remove wild-type N-glycans. Then, CFSE-labelled iWJ-MSC-EV were tested in the context of in vitro capture, agarose-spot migration and matrigel-based tube formation assays, using HUVEC. As a result, we found that the N-glycosylation in iWJ-MSC-EV is critical for interaction with HUVEC cells. iWJ-MSC-EV were captured by HUVEC, stimulating their tube-like formation ability and promoting their recruitment. Conversely, the removal of N-glycans through PNGase-F treatment reduced all of these functional activities induced by native iWJ-MSC-EV. Finally, comparative lectin arrays of iWJ-MSC-EV and PNGase-F-treated iWJ-MSC-EV found marked differences in the surface glycosylation pattern, particularly in N-acetylglucosamine, mannose, and fucose-binding lectins. Taken together, our results highlight the importance of N-glycans in MSC-EV to permit EV–cell interactions and associated functions. Full article

(This article belongs to the Special Issue Study of the Molecular Mechanisms of the Therapeutic Properties of Extracellular Vesicles)

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19 pages, 8710 KiB

Open AccessArticle

Human Multipotent Mesenchymal Stromal Cell–Derived Extracellular Vesicles Enhance Neuroregeneration in a Rat Model of Sciatic Nerve Crush Injury

by Svetlana V. Demyanenko, Maria A. Pitinova, Yulia N. Kalyuzhnaya, Andrey M. Khaitin, Svetlana A. Batalshchikova, Natalya M. Dobaeva, Yulia A. Shevtsova, Kirill V. Goryunov, Egor Y. Plotnikov, Svetlana G. Pashkevich, Gennady T. Sukhikh and Denis N. Silachev

Int. J. Mol. Sci. 2022, 23(15), 8583; https://doi.org/10.3390/ijms23158583 - 02 Aug 2022

Cited by 10 | Viewed by 2999

Abstract

Peripheral nerve injury remains a serious problem for medicine, with no effective method of treatment at the moment. The most prominent example of this problem is neonatal brachial plexus palsy, which results from the stretching of the brachial plexus nerves in the birth or perinatal period. Multipotent mesenchymal cells (MSCs) and the extracellular vesicles (EVs) they produce are known to have a marked neuroprotective effect in central nervous system injuries. We suggested that the use of MSCs-derived EVs may be an effective approach to the regeneration of peripheral nerves after injury. Sciatic nerve injury was modeled in rats via crushing, and then a gel containing MSCs–EVs was applied to the injured area. After 15 and 30 days, a histological, physiological, and functional assessment of nerve, dorsal root ganglia (DRG), and innervated muscles’ recovery was performed. Transplantation of EVs to the area of sciatic nerve injury significantly reduced muscle atrophy as compared to the control group. Functional recovery of the innervated muscles, as measured by the extensor postural thrust test, was revealed 30 days after the surgery. We associate the obtained results with EVs-induced neuroprotective mechanisms, which were expressed in a decrease in apoptotic neuronal death and an increase in regeneration-associated proteins NF-200 and GAP-43, as well as in DRG and damaged nerve. We suggest that the therapeutic scheme we used is efficient for the treatment of acute peripheral nervous system injuries and can be transferred to the clinics. However, additional studies are required for a more detailed analysis of neuroprotection mechanisms. Full article

(This article belongs to the Special Issue Study of the Molecular Mechanisms of the Therapeutic Properties of Extracellular Vesicles)

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Review

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18 pages, 1171 KiB

Open AccessReview

Therapeutic Potential of Extracellular Vesicles in Aging and Age-Related Diseases

by Jorge Sanz-Ros, Cristina Mas-Bargues, Nekane Romero-García, Javier Huete-Acevedo, Mar Dromant and Consuelo Borrás

Int. J. Mol. Sci. 2022, 23(23), 14632; https://doi.org/10.3390/ijms232314632 - 23 Nov 2022

Cited by 6 | Viewed by 3148

Abstract

Aging is associated with an alteration of intercellular communication. These changes in the extracellular environment contribute to the aging phenotype and have been linked to different aging-related diseases. Extracellular vesicles (EVs) are factors that mediate the transmission of signaling molecules between cells. In the aging field, these EVs have been shown to regulate important aging processes, such as oxidative stress or senescence, both in vivo and in vitro. EVs from healthy cells, particularly those coming from stem cells (SCs), have been described as potential effectors of the regenerative potential of SCs. Many studies with different animal models have shown promising results in the field of regenerative medicine. EVs are now viewed as a potential cell-free therapy for tissue damage and several diseases. Here we propose EVs as regulators of the aging process, with an important role in tissue regeneration and a raising therapy for age-related diseases. Full article

(This article belongs to the Special Issue Study of the Molecular Mechanisms of the Therapeutic Properties of Extracellular Vesicles)

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16 pages, 1263 KiB

Open AccessReview

The Emerging Role of Extracellular Vesicles and Autophagy Machinery in NASH—Future Horizons in NASH Management

by Eleni-Myrto Trifylli, Anastasios G. Kriebardis, Evangelos Koustas, Nikolaos Papadopoulos, Melanie Deutsch, Georgios Aloizos, Sotirios P. Fortis, Effie G. Papageorgiou, Ariadne Tsagarakis and Spilios Manolakopoulos

Int. J. Mol. Sci. 2022, 23(20), 12185; https://doi.org/10.3390/ijms232012185 - 12 Oct 2022

Cited by 6 | Viewed by 2372

Abstract

Non-alcoholic fatty liver disease (NAFLD) is considered the most frequent chronic hepatic disease in the general population, while it is the first cause of liver transplantation in the US. NAFLD patients will subsequently develop non-alcoholic steatohepatitis (NASH), which is characterized by aberrant hepatocellular inflammation with or without the presence of fibrosis. The lack of specific biomarkers and therapeutic strategies makes non-alcoholic steatohepatitis (NASH) management a difficult task for clinicians. Extracellular vesicles (EVs) constitute a heterogenic population of vesicles produced by inward or outward plasma-membrane budding. There is an emerging connection between autophagy EVs production, via an unconventional non-degradative procedure. Alterations in the amount of the secreted EVs and the cargo they carry are also involved in the disease progression and development of NASH. Autophagy constitutes a multistep lysosomal degradative pathway that reassures cell homeostasis and survival under stressful conditions, such as oxygen and energy deprivation. It prevents cellular damage by eliminating defected proteins or nοn-functional intracellular organelles. At the same time, it reassures the optimal conditions for the cells via a different mechanism that includes the removal of cargo via the secretion of EVs. Similarly, autophagy machinery is also associated with the pathogenetic mechanism of NAFLD, while it has a significant implication for the progression of the disease and the development of NASH. In this review, we will shed light on the interplay between autophagy and EVs in NASH, the emerging connection of EVs production with the autophagy pathway, and their possible manipulation for developing future therapeutic strategies for NASH. Full article

(This article belongs to the Special Issue Study of the Molecular Mechanisms of the Therapeutic Properties of Extracellular Vesicles)

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17 pages, 736 KiB

Open AccessReview

Update on Extracellular Vesicle-Based Vaccines and Therapeutics to Combat COVID-19

by Tamanna Mustajab, Moriasi Sheba Kwamboka, Da Ae Choi, Dae Wook Kang, Junho Kim, Kyu Ri Han, Yujin Han, Sorim Lee, Dajung Song and Yong-Joon Chwae

Int. J. Mol. Sci. 2022, 23(19), 11247; https://doi.org/10.3390/ijms231911247 - 24 Sep 2022

Cited by 8 | Viewed by 2344

Abstract

The COVID-19 pandemic has had a deep impact on people worldwide since late 2019 when SARS-CoV-2 was first identified in Wuhan, China. In addition to its effect on public health, it has affected humans in various aspects of life, including social, economic, cultural, and political. It is also true that researchers have made vigorous efforts to overcome COVID-19 throughout the world, but they still have a long way to go. Accordingly, innumerable therapeutics and vaccine candidates have been studied for their efficacies and have been tried clinically in a very short span of time. For example, the versatility of extracellular vesicles, which are membrane-bound particles released from all types of cells, have recently been highlighted in terms of their effectiveness, biocompatibility, and safety in the fight against COVID-19. Thus, here, we tried to explain the use of extracellular vesicles as therapeutics and for the development of vaccines against COVID-19. Along with the mechanisms and a comprehensive background of their application in trapping the coronavirus or controlling the cytokine storm, we also discuss the obstacles to the clinical use of extracellular vesicles and how these could be resolved in the future. Full article

(This article belongs to the Special Issue Study of the Molecular Mechanisms of the Therapeutic Properties of Extracellular Vesicles)

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